This is a renewal application of the program project studying therapeutic and diagnostic issues in Alzheimer's disease (AD) since 1980. Studies are proposed that are both a continuation and an extension of previous work. Based on animal data derived from the Alzheimer's Disease Research Center, combined therapies with cholinergic and adronergic agents are now proposed. In addition, preclinical studies are included that are designed to elucidate the basis of the finding that the addities of a noradrengic deficit to animals with a nucleus basalis lesion causes a complete loss in the ability of cholinergic agents to otherwise normalize the behavior of these animals. In depth studies of the noradrenergic/cholinergic relationship are now proposed that will include electrophysio-logical parameters. The Alzheimer's Disease Assessment Scale (ADAS) was developed, as perviously proposed, and is now widely used. However, experience with that scale indicates that this scale loses the ability to document change in the end stage of the disease. A new goal of this application is to develop an assessment instrument for late stage disease. The elucidation of markers that will detect the earliest manifestation of Alzheimer's disease is also proposed. A series of biological markers including scopolamine challenge, change in ventricular brain ratio, acoustic thresholds, and CSF somatostatin will be studied in first degree relatives of Alzheimer's probands who are over the age of 65. This high risk group constitutes an ideal population to determine if any of these markers will predict the subsequent development of frank symptoms of Alzheimer's dementia. Such a marker would facilitate the use of potential therapeutic agents in the earlier stage of the disease, and provide invaluable information for linkage studies that necessitate the most accurate marker of the Alzheimer's disease phenotype.